Rosuvastatin and process for its preparation is disclosed in U.S. Pat. No. 5,260,440 incorporated herein by reference. The process disclosed therein involves four distinct chemical steps and the generation of the phosphorane side chain requires expensive reagents and the process is both uneconomical and time consuming, and statin compounds preparation through wittig reaction leads to the formation of ‘Z’ isomer approximately around 20% as well as poor solubility of calcium salt of rosuvastatin has been observed in an aqueous methanol with this process, which is due to the formation of sodium chloride byproducts. This is a major drawback in the synthesis of calcium salt of rosuvastatin, hence is not suitable for commercial production.
Atorvastatin calcium and process for its preparation is disclosed in U.S. Pat. No. 5,273,995 incorporated herein by reference, discloses the enationmer having the R form of the ring-opened acid of trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N-4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide. i.e., [R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamineo) carbonyl]-1H-pyrrole-1-heptanoic acid.
Fluvastatin sodium and process for its preparation is disclosed in U.S. Pat. No. 4,739,073 incorporated herein by reference, discloses fluvastatin as a racemate and its pharmaceutically acceptable salts especially sodium salt. This patent also discloses process for the preparation of fluvastatin, which involves treating (E)-3-[3′-(4′fluorophenyl)-1′-(1″-methylethyl)indol-2-yl)-2-propenal with methyl acetoacetate in presence of a strong base like n-butyl lithium and sodium hydride in tetrahydrofuran to get Methyl-(±)-(E)-7-[3′-(4″-fluorophenyl)-1′-(1″-methylethyl)-indol-2′-yl]-5-hydroxiy-3-oxo-hept-6-enoate which is further reacted with triethyl borane, tetrahydrofuran and sodium borohydride to get (±)-Erythro-7-(4″-Fluorophenyl)-1′-(1″-methylethyl)-indol-2′-yl]-3,5-dihydroxyhept-6-enoate, methyl ester followed by treated with anhydrous methanol to get the methyl(±)-erythro-(E)-3,5-dihydroxy-7-[3′-(4″-fluorophenyl)-1′-(1″-methylethyl)indol-2′-yl]hept-6-enoate(diol ester) which is purified by the column chromatography. The diol ester compound is hydrolysed with aqueous sodium hydroxide solution to get the fluvastatin sodium.
Pitavastatin and process for its preparation is disclosed in EP patent 304063 and EP 1099694 and in the publication by N. Miyachi et al. in Tetrahedron Letters 1993, Vol. 34, page no. 8267-8270 and by K. Takahashi et al. in Bull. Chem. Soc. Jpn. 1995, Vol. 68, 2649-2656. These publications describe the synthesis of Pitavastatin in great detail.
Our earlier Indian patent application 782/CHE/2005 published in Indian patent Journal on 18th Aug. 2006 incorporated herein by reference, discloses a novel process for the preparation of rosuvastatin calcium. The said patent also discloses following organic amine salt of rosuvastatin, cyclic amines such as cyclopropyl amine, cyclo pentyl amine, cyclo hexyl amine, dicyclohexyl amine, pyrrolidine or morpholine or alkylamines such as isopropyl amine, diisopropyl amine, phenyl propyl amine, tertiary butyl amine and its analogues. It further discloses the purification of organic amine salts in acetone, acetonitrile or mixture of acetonitrile and isopropyl alcohol.
Tetrahedron Letters, Vol. 31, No. 18, pp 2545-2548, 1990 incorporated herein by reference, discloses stereo selective synthesis of HMG-COA reductase inhibitors through lactone intermediate i.e., corresponding protected ester compound on reaction with trifluoroacetic acid. The said journal discloses the pyridine derivative compound as HMG-COA reductase inhibitor and disclosed various synthetic processes (i.e., by wittig and wittig homer reaction), The said journal also discloses a process for the preparation of aldehyde side chain of HMG-CoA reductase inhibitors.
U.S. Pat. No. 4,977,279 incorporated herein by reference, this patent discloses derivatives of 3-demethylmevalonic acid. This patent also teaches the process for the preparation of pyridine and pyrimidine derivatives of demethylmevalonic acid.
U.S. Pat. No. 4,970,313 incorporated herein by reference, discloses process for the preparation of optically active 3-demethylmevalonic acid derivatives via β-hydroxy lactone and also disclosed the protected aldehyde side chain of Statin compounds.
The alternate method for the preparation of olefinic compounds is Julia classical olefination, Julia modified olefination, Julia modified olefination process for the preparation of HMG CoA Reductase inhibitors, is disclosed and claimed in U.S. Pat. No. 6,875,867 incorporated herein by reference, in this patent chiral diol sulfone (aliphatic chain of statins) intermediates used for the preparation of HMG CoA reductase inhibitors, the disclosed chiral diol sulfones are not stable and low yields were observed when using aliphatic chiral diol sulfones when compare to aromatic sulfone derivatives.
International publication WO 2001/60804 incorporated herein by reference, discloses a process for the preparation of amorphous form of rosuvastatin calcium from amine salt which gives high pure rosuvastatin calcium. The amine salt can be recrystallized to get highest purity. The said patent also discloses a process for the preparation of amine salt from an acid.
International publication WO 2004/014872 incorporated herein by reference, discloses a process for the preparation of calcium salt of rosuvastatin. The process comprises, mixing of calcium chloride with a solution of water soluble salt of rosuvastatin like sodium salt, methylamine salt, tris salt and ammonium salt wherein the process parameters are selected to give a product which demonstrates improved efficiency of filtration.
International publication WO2004/108691 incorporated herein by reference, discloses a process for an improved production of rosuvastatin calcium salt which discloses the usage of calcium chloride, calcium bromide and calcium acetate as a calcium source for the preparation of rosuvastatin calcium.
International publication WO 2005/042522 incorporated herein by reference, the said patent claims crystalline form of dihydroxy and olefin compound of rosuvastatin ester.
International publication WO 2005/054207 incorporated herein by reference, discloses an alternate process for the preparation of rosuvastatin and its intermediates via wittig reagents. The process involved the condensation of wittig reagent like triphenyl[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-ylmethyl]phosphonium bromide or other reagent with aldehyde side chain compound tert-butyl2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dixan-4-yl}acetate in a suitable solvent and in presence of a base to give tertiarybutyl ester compound of rosuvastatin which is further converted into free acid then to calcium salt by contacting calcium source. This process suffers from quality aspects as Z isomer formation is high (i.e., approximately 20%) in witting reactions.
International publication WO 2005/077916 incorporated herein by reference, discloses crystalline cyclohexyl ammonium, diisopropyl ammonium, isopropyl ammonium, dicyclohexyl ammonium(S)-(+)-methylbenzyl ammonium salts of rosuvastatin and process for their preparation. The said patent also discloses process for the preparation of amorphous rosuvastatin calcium from generic amine salt of rosuvastatin and the PXRD pattern of amorphous form of rosuvastatin calcium.
International publication WO 2006/035277 incorporated herein by reference, discloses a process for the preparation of amorphous form of rosuvastatin calcium and novel crystalline form A of rosuvastatin calcium and also disclosed the PXRD pattern of both crystalline and amorphous form of rosuvastatin calcium salt.
International publication WO 2006/079611 incorporated herein by reference, discloses a novel crystalline form B and C of rosuvastatin calcium salt hydrates and process for their preparation. The disclosed PXRD pattern of the Form C is similar to the disclosed amorphous form of rosuvastatin calcium.
International publication WO 2006/136407 incorporated herein by reference, disclosed a pure amorphous form of rosuvastatin calcium having HPLC purity more than 99.9% and free from any traces of alkali metal impurities. The said patent also discloses process for the preparation of amorphous rosuvastatin calcium, which comprises of reacting the tertiary butyl ester of rosuvastatin with organic amine salt to get pure amorphous rosuvastatin calcium. The international publication WO 2001/60804 is also disclosed process for the preparation of pure amorphous rosuvastatin calcium from organic amine salt compound.
International publication WO 2007/000121 incorporated herein by reference, discloses a process for the preparation of hemi-calcium salt of rosuvastatin in crystalline or amorphous solid state. The process comprises of hydrolyzing the alkyl ester or amides of rosuvastatin and converting the obtained alkali salt into calcium salt of rosuvastatin by reacting with suitable calcium source in aqueous medium followed by extracting the crude rosuvastatin calcium into a solvent partially miscible with water, washing with water and isolating by cooling and filtration or by adding anti-solvent and filtration or spray drying into the stream of inert gas.
International publication WO 2007/040940 incorporated herein by reference, discloses a process for the preparation of diasteriomerically pure rosuvastatin and intermediates.
International publication WO 2007/041666 incorporated herein by reference, discloses a process for the preparation of rosuvastatin calcium by employing witting homer reaction.
It is, therefore, desirable to provide an efficient process for the preparation of statins which improves the economics by employing less expensive reagents and is more productive compare to the known processes.
The present invention provides a novel and advantageous process for the preparation of calcium salt of statins which solves solubility problem of the compound in an aqueous methanol and gives free flow solid of calcium salt. The present invention uses calcium acetate instead of calcium chloride so the byproduct is sodium acetate, which is highly soluble in water. So the obtained compound is freely soluble in methanol.
The present invention provides a process which involves less number of steps, without isolation of intermediate, eco-friendly, easy to scale-up and commercially viable for the preparation of statins and its pharmaceutically acceptable salts thereof.
Disadvantages of the Prior Art Processes:
                Usage of hazardous reagents like phosphorous trihalides or phosphorous oxyhalides.        Usage of strong base like LDA/n-BuLi followed by usage of Na/Hg in Julia classical olefination reactions, which are highly pyrophoric in nature, hence those are not recommended for commercial scale up.        Usage of strong base like LDA/n-BuLi in Julia modified olefination reactions, which are highly pyrophoric in nature, hence those are not recommended for commercial scale up.        Chiral diol sulfone compounds which are prepared as per the procedure given in U.S. Pat. No. 6,875,867 are unstable intermediates.        Poor solubility of calcium salt compound of formula-1 in an aqueous methanol.        Z isomer content is high in the rosuvastatin calcium prepared as per the prior art.        